Benign prostatic hyperplasia, also known as benign prostatic hypertrophy or BPH, is an illness typically affecting men over fifty years of age, increasing in severity with increasing age. The symptoms of the condition include, but are not limited to, increased difficulty in urination and sexual dysfunction. These symptoms are induced by enlargement, or hyperplasia, of the prostate gland. As the prostate increases in size, it impinges on free-flow of fluids through the male urethra. Concommitantly, the increased noradrenergic innervation of the enlarged prostate leads to an increased adrenergic tone of the bladder neck and urethra, further restricting the flow of urine through the urethra.
Recent advances in molecular biology have identified the alpha 1a adrenoceptor subtype as the predominant alpha 1 receptor that mediates the contraction of prostate and lower urinary tract smooth muscle. Several classes of compounds have been disclosed to be selective alpha 1a adrenergic receptor antagonists useful for treating BPH. For example, WO 96/14846, WO 97/17969 and WO 97/42956 each disclose certain dihydropyrimidine derivatives (e.g., certain 1,2,3,6-tetrahydro-2-oxo-pyrimidine derivatives) which are selective antagonists for the human alpha 1a receptor and useful for treatment of BPH, impotency, cardiac arrhythmia, and other diseases where antagonism of the alpha 1a receptor may be useful.
Compound A is a potent and selective antagonist of the alpha 1a adrenergic receptor antagonist and is useful in the treatment of BPH. More particularly, the compound is (4S,5S)-4-(3,4-difluorophenyl)-N-[3-[4-(4-fluorophenyl)-1-piperidinyl]prop yl]-5-methyl-2-oxo-3-oxazolidine carboxamide and has the formula: ##STR2##
Because free base Compound A can be sensitive to bases and, with the nitrogen atom not being protonated, can also be susceptible to oxidation, a pharmaceutically acceptable salt of Compound A is desirable. Preparation of an acceptable salt of Compound A suitable for pharmaceutical development has been problematic. Numerous attempts to isolate a crystalline salt formn of Compound A failed as only amorphous salts could be isolated. A crystalline salt which was isolated had too low a melting point to be practical for processing into pharmaceutical compositions.
These problems were solved by identification of the crystalline pharmaceutically acceptable benzenesulfonic acid salt of Compound A of the present invention.